Cysteamine attenuates the decreases in TrkB protein levels and the anxiety/depression-like behaviors in mice induced by corticosterone treatment.

Kutiyanawalla A, Terry AV, Pillai A - PLoS ONE (2011)

Bottom Line:
Cysteamine administration (150 mg/kg/day, through drinking water) for 21 days significantly ameliorated chronic corticosterone-induced decreases in TrkB protein levels in frontal cortex and hippocampus.Finally, mice deficient in TrkB, showed a reduced response to cysteamine in behavioral tests, suggesting that TrkB signaling plays an important role in the antidepressant effects of cysteamine.The animal studies described here highlight the potential use of cysteamine as a novel therapeutic strategy for glucocorticoid-related symptoms of psychiatric disorders.

Objective: Stress and glucocorticoid hormones, which are released into the circulation following stressful experiences, have been shown to contribute significantly to the manifestation of anxiety-like behaviors observed in many neuropsychiatric disorders. Brain-derived neurotrophic factor (BDNF) signaling through its receptor TrkB plays an important role in stress-mediated changes in structural as well as functional neuroplasticity. Studies designed to elucidate the mechanisms whereby TrkB signaling is regulated in chronic stress might provide valuable information for the development of new therapeutic strategies for several stress-related psychiatric disorders.

Materials and methods: We examined the potential of cysteamine, a neuroprotective compound to attenuate anxiety and depression like behaviors in a mouse model of anxiety/depression induced by chronic corticosterone exposure.

Results: Cysteamine administration (150 mg/kg/day, through drinking water) for 21 days significantly ameliorated chronic corticosterone-induced decreases in TrkB protein levels in frontal cortex and hippocampus. Furthermore, cysteamine treatment reversed the anxiety and depression like behavioral abnormalities induced by chronic corticosterone treatment. Finally, mice deficient in TrkB, showed a reduced response to cysteamine in behavioral tests, suggesting that TrkB signaling plays an important role in the antidepressant effects of cysteamine.

Conclusions: The animal studies described here highlight the potential use of cysteamine as a novel therapeutic strategy for glucocorticoid-related symptoms of psychiatric disorders.

pone-0026153-g007: Effects of cysteamine in chronic corticosterone-treated mice in the Open Field test.CD-1 male mice were treated for 7 weeks with vehicle (0.45% hydroxypropyl-β-cyclodextrin) or corticosterone (CORT; 35 ug/ml) in the presence or absence of cysteamine (CYS; 150 mg/kg/day) during the last three weeks of the corticosterone treatment. (A) Mean total of the time-spent in the center for the entire session, (B) the ambulatory counts for each 5 min period, (C) the total ambulatory distance and (D) the ambulatory distance in the center over total. Values plotted are mean ± SEM (n = 8–10 per group). Bonferroni's post hoc test. *p<0.05 versus vehicle and #p<0.05 versus CORT.

Mentions:
Fig 7 illustrates the effects of drug treatment on open field locomotor activity. Mice treated with corticosterone for 7 weeks showed significant changes in open field activity behavior. Statistical analysis of the data on time spent in center by two-way ANOVA with corticosterone/vehicle pretreatment and cysteamine/vehicle as main effects revealed a significant main effect of treatment [F(1,30) = 5.675; p<0.01] and pretreatment x treatment interaction [F(1,30) = 6.72; p<0.01], but no significant effect of pretreatment [F(1,30) = 2.198; p = 0.148]. Subsequent Post hoc analysis showed that corticosterone-treated mice spent less time in the center as compared to vehicle-treated mice (Fig 7A; p<0.05). Interestingly, cysteamine treatment reversed this anxiety-related behavior (p<0.01 verses corticosterone group in time spent in the center). There was clear evidence of habituation to the open field environment in all test groups as indicated by the diminishing horizontal counts over time (Fig 7B). Two-way ANOVA revealed a significant main effect of treatment [F(3,177) = 9.166; p<0.0001] and time [F(5,177) = 61.49; p<0.0001] without a significant treatment x time interaction [F(15,177) = 0.111; p = 1.0]. However, post hoc analysis did not show any significant change in ambulatory counts between treatment groups. In addition, we did not find any significant change in total ambulatory distance between treatment groups (Fig 7C). Next, we examined the ratio of ambulatory distance in center to total distance. Two-way ANOVA showed a significant main effect of treatment [F(1,30) = 4.512; p<0.01] and pretreatment x treatment interaction [F(1,30) = 9.481; p<0.001], but no significant effect on pretreatment [F(1,30) = 1.878; p = 0.182]. Post-hoc analysis Corticosterone-treated mice showed a decrease in the ratio (Fig 7D; p<0.05) and cysteamine treatment reversed this behavior (p<0.05). These data suggest that cysteamine treatment reverses chronic corticosterone-induced changes in open field activity behavior in mice.

pone-0026153-g007: Effects of cysteamine in chronic corticosterone-treated mice in the Open Field test.CD-1 male mice were treated for 7 weeks with vehicle (0.45% hydroxypropyl-β-cyclodextrin) or corticosterone (CORT; 35 ug/ml) in the presence or absence of cysteamine (CYS; 150 mg/kg/day) during the last three weeks of the corticosterone treatment. (A) Mean total of the time-spent in the center for the entire session, (B) the ambulatory counts for each 5 min period, (C) the total ambulatory distance and (D) the ambulatory distance in the center over total. Values plotted are mean ± SEM (n = 8–10 per group). Bonferroni's post hoc test. *p<0.05 versus vehicle and #p<0.05 versus CORT.

Mentions:
Fig 7 illustrates the effects of drug treatment on open field locomotor activity. Mice treated with corticosterone for 7 weeks showed significant changes in open field activity behavior. Statistical analysis of the data on time spent in center by two-way ANOVA with corticosterone/vehicle pretreatment and cysteamine/vehicle as main effects revealed a significant main effect of treatment [F(1,30) = 5.675; p<0.01] and pretreatment x treatment interaction [F(1,30) = 6.72; p<0.01], but no significant effect of pretreatment [F(1,30) = 2.198; p = 0.148]. Subsequent Post hoc analysis showed that corticosterone-treated mice spent less time in the center as compared to vehicle-treated mice (Fig 7A; p<0.05). Interestingly, cysteamine treatment reversed this anxiety-related behavior (p<0.01 verses corticosterone group in time spent in the center). There was clear evidence of habituation to the open field environment in all test groups as indicated by the diminishing horizontal counts over time (Fig 7B). Two-way ANOVA revealed a significant main effect of treatment [F(3,177) = 9.166; p<0.0001] and time [F(5,177) = 61.49; p<0.0001] without a significant treatment x time interaction [F(15,177) = 0.111; p = 1.0]. However, post hoc analysis did not show any significant change in ambulatory counts between treatment groups. In addition, we did not find any significant change in total ambulatory distance between treatment groups (Fig 7C). Next, we examined the ratio of ambulatory distance in center to total distance. Two-way ANOVA showed a significant main effect of treatment [F(1,30) = 4.512; p<0.01] and pretreatment x treatment interaction [F(1,30) = 9.481; p<0.001], but no significant effect on pretreatment [F(1,30) = 1.878; p = 0.182]. Post-hoc analysis Corticosterone-treated mice showed a decrease in the ratio (Fig 7D; p<0.05) and cysteamine treatment reversed this behavior (p<0.05). These data suggest that cysteamine treatment reverses chronic corticosterone-induced changes in open field activity behavior in mice.

Bottom Line:
Cysteamine administration (150 mg/kg/day, through drinking water) for 21 days significantly ameliorated chronic corticosterone-induced decreases in TrkB protein levels in frontal cortex and hippocampus.Finally, mice deficient in TrkB, showed a reduced response to cysteamine in behavioral tests, suggesting that TrkB signaling plays an important role in the antidepressant effects of cysteamine.The animal studies described here highlight the potential use of cysteamine as a novel therapeutic strategy for glucocorticoid-related symptoms of psychiatric disorders.

Objective: Stress and glucocorticoid hormones, which are released into the circulation following stressful experiences, have been shown to contribute significantly to the manifestation of anxiety-like behaviors observed in many neuropsychiatric disorders. Brain-derived neurotrophic factor (BDNF) signaling through its receptor TrkB plays an important role in stress-mediated changes in structural as well as functional neuroplasticity. Studies designed to elucidate the mechanisms whereby TrkB signaling is regulated in chronic stress might provide valuable information for the development of new therapeutic strategies for several stress-related psychiatric disorders.

Materials and methods: We examined the potential of cysteamine, a neuroprotective compound to attenuate anxiety and depression like behaviors in a mouse model of anxiety/depression induced by chronic corticosterone exposure.

Results: Cysteamine administration (150 mg/kg/day, through drinking water) for 21 days significantly ameliorated chronic corticosterone-induced decreases in TrkB protein levels in frontal cortex and hippocampus. Furthermore, cysteamine treatment reversed the anxiety and depression like behavioral abnormalities induced by chronic corticosterone treatment. Finally, mice deficient in TrkB, showed a reduced response to cysteamine in behavioral tests, suggesting that TrkB signaling plays an important role in the antidepressant effects of cysteamine.

Conclusions: The animal studies described here highlight the potential use of cysteamine as a novel therapeutic strategy for glucocorticoid-related symptoms of psychiatric disorders.